Grid potential analysis,virtual screening studies and ADME/T profiling on N‐arylsulfonylindoles as anti‐HIV‐1 agents

A grid potential analysis employing a novel approach of 3D quantitative structure–activity relationships (QSAR) as AutoGPA module in MOE2009.10 was performed on a dataset of 42 compounds of N‐arylsulfonylindoles as anti‐HIV‐1 agents. The uniqueness of AutoGPA module is that it automatically builds the 3D‐QSAR model on the pharmacophore‐based molecular alignment. The AutoGPA‐based 3D‐QSAR model obtained in the present study gave the cross‐validated Q² value of 0.588, r²_pred value of 0.701, r²_m statistics of 0.732 and Fisher value of 94.264. The results of 3D‐QSAR analysis indicated that hydrophobic groups at R₁ and R₂ positions and electron releasing groups at R₃ position are favourable for good activity. To find similar analogues, virtual screening on ZINC database was carried out using generated AutoGPA‐based 3D‐QSAR model and showed good prediction. In addition to those mentioned earlier, in‐silico ADME absorption, distribution, metabolism and excretion profiling and toxicity risk assessment test was performed, and results showed that majority of compounds from current dataset and newly virtually screened hits generated were within their standard limit. Copyright © 2013 John Wiley & Sons, Ltd.     

Quantitative structure‐retention relationships of the chromatographic retentions of phthalic acid ester contaminants in foods

The harmful health effects caused by phthalic acid esters have been supported from the increasing scientific evidence, developing the efficient methodologies to monitor the levels of phthalic acid esters in various foods become especially important from the aspects of human exposure assessment and their migration mechanistic understanding. In this study, quantitative structure‐retention relationship studies on both the gas and liquid chromatographic retention times of 23 phthalic acid esters were performed by genetic function approximation, and the optimal quantitative structure‐retention relationship models (r² > 0.980, r²_CV > 0.960, and r²_pred > 0.865) passed the statistical tests of cross‐validation, randomization, external prediction, Roy′ r_m² metrics, Golbraikh‐Tropsha′ criteria and applicability domain. The established predictive models elucidate the structural requirements for the retention of phthalic acid esters over different chromatographic columns, which were finally used to predict the retention times of 11 new phthalic acid esters. Hopefully, this work could provide useful guidelines for better understanding and accurate prediction of the retention behavior of undetermined phthalic acid esters when lacking standard samples or under poor experimental conditions, and make the simultaneous identification and quantification of numerous phthalic acid esters possible.     

Generalized morse analytic function for the “true” diatomic potential of the RKR type

The problem of the representation of the RKR (or IPA) diatomic potential by a simple analytic function is considered. This old problem has for a fairly good solution the Coxon-Hajigeorgiou function U(x) = D[1 - exp-f_n(x)]² with f_n(x) = Σ a_mx^m. The problem of the determination of the disposable parameters a₁ … a_n [in order that U(r) fits the given RKR potential] is reduced to that of a set of linear equations in a_m where a standard least-squares technique is used. The application to several states (ground or excited) of several molecules shows that a fairly “good” fit is obtained for n ～ 10, even for the state XO_g—I₂ bounded by 109 vibrational levels, for which the RKR potential is defined by the coordinates of 219 points. It is shown that the percentage deviation |U(r)^RKR - U(r)| throughout the range of r values is about 0.04% for XΣ? Li₂, 0.0005% for XΣ? HCl, 0.06% for XO_g? I₂, and 0.05% for BO_u? I₂ (as examples). This approach shows the same success for deep and shallow potentials. The comparison of the computed E_v (vibrational energy) and B_v (rotational constant) with their corresponding experimental values shows that a good agreement is reached even for high vibrational levels close to the dissociation. © John Wiley & Sons, Inc.     

Tunable Keplerate Type‐Cluster “Mo132” Cavity with Dicarboxylate Anions

The internal functionalization of the Keplerate‐type capsule Mo₁₃₂ has been carried out by ligand exchange leading to the formation of glutarate and succinate containing species isolated as ammonium or dimethylammonium salts. Solution NMR analysis is consistent with asymmetric inner dicarboxylate ions containing one carboxylato group grafted onto the inner side of the spheroidal inorganic shell while the second hangs toward the center of the cavity. Such a disposition has been confirmed by the single‐crystal X‐ray diffraction analysis of the glutarate containing {Mo₁₃₂} species. A detailed NMR solution study of the ligand‐exchange process allowed determining the binding constant K_L of acetate (AcO^?), succinate (HSucc^?) or glutarate (HGlu^?) ligands at the 30 inner coordinating sites, which vary such as K<K<K‐supported by the associated thermodynamic parameters Δ_rS* and Δ_rH*. Such a variation is mainly explained by a positive entropic gain attenuated by unfavorable steric effect. Furthermore, these results are completed by ¹H DOSY and ¹H EXSY NMR experiments which are in agreement with bulky guests firmly trapped within the cavity. At last, variable temperature ¹H NMR study below 290 K revealed a striking line broadening occurring abruptly within a 5 K range. Such an effect appears closely related to the presence of the ammonium cations suspected to be present within the cavity and then has been interpreted as an inner‐phase transition leading to a frozen state.     

QSAR study of peptide drugs by 3D-HoVAIF

By applying a three-dimensional holographic vector of the atomic interaction field (3D-HoVAIF) to express the structure of three classical peptide drugs, quantitative structure activity relationship (QSAR) models are built by the multiple linear regression. The accuracy of the proposed model is illustrated using Q _LOO ² (cross-validation) and r ² (test set validation). Moreover, the r _m ² metrics is used to further refine the predictive ability of the developed QSAR models. The results show that 3D-HoVAIF, due to the high predictive ability, offers a useful alternative to the costly and time-consuming experiments determining the bioactivity of peptide drugs.     

Effect of annealing on the structure and properties of poly(vinylidene fluoride) β‐form films

Oriented poly(vinylidene fluoride) (PVDF) films consisting of β crystals were prepared by the solid‐state coextrusion (SC) of a gel film near the melting temperature (T_m) and by conventional cold tensile drawing (TD) of a melt‐quenched film. These films were annealed over the temperature range of 75–190 °C (below and above the static T_m) while the sample length was kept constant or constant loads were applied. After annealing with the sample length kept constant, the dynamic Young's modulus markedly decreased because of the relaxation of oriented amorphous chains, as shown by infrared spectroscopy. In contrast, annealing under a constant load improved the chain orientation in both the crystalline and amorphous regions, resulting in an increase in the modulus from an initial 10.5 to 14.3 GPa for the SC and from an initial 3.3 to 4.8 GPa for the TD. The SC, annealed at 190 °C with a constant load corresponding to an initial tension of 200 MPa, exhibited an extreme crystalline‐chain orientation of 0.998 and a modulus of 14.3 GPa, among the highest values ever reported for PVDF. Although the remanent polarization (P_r) of the TD increased slightly from the initial 62 to 68 mC/m², P_r of the SC stayed constant at 100 mC/m² independently of the annealing conditions. This suggests that the P_r value of 100 mC/m² approached the equilibrium value for this PVDF sample containing 3.5 mol % structural defects. Therefore, although the modulus and P_r of the TD increased slightly with annealing, the maximum values achieved by annealing were markedly lower than those of the SC and annealed SC. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 1701–1712, 2003     

Random ethene/propene copolymerization from a catalyst system based on a “constrained geometry” half‐sandwich complex

Ethene/propene copolymerizations were performed in solution with a single centre catalyst system composed of a “constrained geometry” half‐sandwich organometallic complex {η¹: η⁵‐[(tert‐butylamido)dimethylsilyl](2,3,4,5‐tetramethyl‐1‐cyclopentadienyl)}titanium dichloride, and methylaluminoxane. The statistical treatment of polymerization data allowed to determine the reactivity ratios for ethene and propene: r_E = 1.35 ± 0.09, r_P = 0.82 ± 0.05, r_Er_P = 1.10 ± 0.14. This catalyst system promotes an almost random distribution of ethene and propene and gives rise to values of r_P and r_E very similar to each other.     

2D and 3D‐QSAR studies on antiproliferative thiazolidine analogs

Two‐dimensional (2D) and three‐dimensional (3D) quantitative structure–activity relationships (QSARs) of 22 thiazolidine analogs with antiproliferative activity expressed as pIC₅₀, which is defined as the negative value of the logarithm of necessary molar concentration of these compounds to cause 50% growth inhibition against melanoma cell lines WM‐164, have been studied by using a combined method of the DFT, MM2 and statistics for 2D, as well as the comparative molecular field analysis (CoMFA) method for 3D. The established 2D‐QSAR model in training set comprised of random 18 compounds shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient (R = 0.832) and the square of the cross‐validation coefficient (q² = 0.803). The same model was further applied to predict pIC₅₀ values of the four compounds in the test set, and the resulting R reaching 0.784, further confirms that this 2D‐QSAR model has high predictive ability. The 3D‐QSAR model also shows good correlative and predictive capabilities in terms of R² (0.956) and q² (0.615) obtained from CoMFA model. Further, the robustness of the CoMFA model was verified by bootstrapping analysis (100 runs) with R (0.979) and SD_bs (0.056). It is very interesting to find that the results from 2D‐ and 3D‐QSAR analyses accord with each other, and they all show that the steric interaction plays a crucial role in determining the cytotoxicities of the compounds, and that selecting a moderate‐size or appropriate‐hydrophobicity substituent R as well as increasing the negative charges of C₄ on phenyl ring at the same time are advantageous to improving the cytotoxicity. Such results can offer some useful theoretical references for directing the molecular design and understanding the action mechanism of this kind of compound with antiproliferative activity. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

DFT‐based QSAR study and molecular design of AHMA derivatives as potent anticancer agents

A quantitative structure–activity relationship (QSAR) of 3‐(9‐acridinylamino)‐5‐hydroxymethylaniline (AHMA) derivatives and their alkylcarbamates as potent anticancer agents has been studied using density functional theory (DFT), molecular mechanics (MM+), and statistical methods. In the best established QSAR equation, the energy (E_NL) of the next lowest unoccupied molecular orbital (NLUMO) and the net charges (Q_FR) of the first atom of the substituent R, as well as the steric parameter (MR₂) of subsituent R₂ are the main independent factors contributing to the anticancer activity of the compounds. A new scheme determining outliers by “leave‐one‐out” (LOO) cross‐validation coefficient (q) was suggested and successfully used. The fitting correlation coefficient (R²) and the “LOO” cross‐validation coefficient (q²) values for the training set of 25 compounds are 0.881 and 0.829, respectively. The predicted activities of 5 compounds in the test set using this QSAR model are in good agreement with their experimental values, indicating that this model has excellent predictive ability. Based on the established QSAR equation, 10 new compounds with rather high anticancer activity much greater than that of 34 compounds have been designed and await experimental verification. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

The influence of total monomers concentration and polymerization solvent on the “reactivity” of ω-(p-vinylbenzyl ether) macromonomers of poly(2,6-dimethyl-1,4-phenylene oxide)

The influence of the total monomers concentration and of the copolymerization solvent on the reactivity ratio, r₁, of methyl methacrylate (MMA) (M₁) ω-(p-vinylbenzyl ether) macromonomer of poly(2,6-dimethyl-1,4-phenylene oxide) (PPO–VBE) (M₂) monomer pair was investigated. For two different molecular weights of PPO-VBE macromonomers: M _n = 15,200 and M _n = 5,100, the determined reactivity ratio, r₁, decreases with the increase in macromonomer concentration. Therefore the reactivity of the macromonomer, 1/r₁, follows the opposite trend. The influence of monomers concentration on r₁ is higher for higher molecular weight macromonomers. The nature of polymerization solvent also affects the value of reactivity ratio, r₁. Micelle formation was demonstrated by ¹H-NMR spectroscopy performed on the resulting graft copolymers in different solvent mixtures. An attempt to explain the observed concentration and solvent effects based on the partition of comonomer concentrations between the bulk of solvent and around the growing chain is presented. Based on this explanation, the determined r₁ represents a product of the partition coefficient, k, and the true reactivity ratio, r₁⁰.     

Binding conformations,QSAR, and molecular design of Alkene‐3‐quinolinecarbonitriles as Src inhibitors

A theoretical study on binding orientations and quantitative structure–activity relationship (QSAR) of a novel series of alkene‐3‐quinolinecarbonitriles acting as Src inhibitors has been carried out by using the docking study and three‐dimensional QSAR (3D‐QSAR) analyses. The appropriate binding orientations and conformations of these compounds interacting with Src kinase were revealed by the docking studies, and the established 3D‐QSAR models show significant statistical quality and satisfactory predictive ability, with high R² values and q² values: comparative molecular field analysis (CoMFA) model (q² = 0.748, R² = 0.972), comparative molecular similarity indices analysis (CoMSIA) model (q² = 0.731, R² = 0.987). The systemic external validation indicated that both CoMFA and CoMSIA models possessed high predictive powers with $ R{^2}_{\!\!\!\rm pred} $ values of 0.818 and 0.892, $ {r^2}_{\!\!\!\rm m} $ values of 0.879 and 0.886, $ {r^2}_{\!\!\!\rm m(LOO)} $ values of 0.874 and 0.874, $ r^2_{\rm m(overall)} $ values of 0.879 and 0.885, respectively. Several key structural features of the compounds responsible for inhibitory activity were discussed in detail. Based on these structural factors, eight new compounds with quite higher predicted Src‐inhibitory activities have been designed and presented. We hope these theoretical results can offer some valuable references for the pharmaceutical molecular design as well as the action mechanism analysis. © 2012 Wiley Periodicals, Inc.